Mesalamine

Description

Each MESALAMINE delayed-release capsule for oral administration contains four 100 mg tablets of mesalamine, an aminosalicylate with the chemical name 5-amino-2-hydroxybenzoic acid. The formulation includes an acrylic-based resin, specifically a methacrylic acid and methyl methacrylate copolymer (Eudragit S), which is designed to dissolve at a pH of 7 or greater. This property allows for the release of mesalamine in the terminal ileum and beyond, providing topical anti-inflammatory action in the colon.

Inactive ingredients in each capsule comprise colloidal silicon dioxide, dibutyl sebacate, ferric oxide red (3.44 mg), ferric oxide yellow (0.62 mg), lactose monohydrate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer (Eudragit S), polyethylene glycol, povidone, sodium starch glycolate, talc, and hydroxypropyl methylcellulose (HPMC).

Uses and Indications

This drug is indicated for the treatment of mildly to moderately active ulcerative colitis in patients aged 5 years and older. Additionally, it is indicated for the maintenance of remission of ulcerative colitis in adults.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

Healthcare professionals should adhere to the following guidelines for the administration of MESALAMINE delayed-release capsules.

Prior to initiating treatment, it is essential to evaluate the patient's renal function. MESALAMINE delayed-release capsules can be taken with or without food. Capsules must be swallowed whole; they should not be cut, broken, crushed, or chewed. For patients who have difficulty swallowing capsules, the capsules may be opened, and the inner tablets can be swallowed. It is also important for patients to drink an adequate amount of fluids during treatment.

For the treatment of mildly to moderately active ulcerative colitis, the recommended dosage for adults is 800 mg, which corresponds to two 400 mg capsules, taken three times daily for a duration of 6 weeks. For pediatric patients aged 5 years or older, dosing should be determined based on the weight-based dosing table provided in the full prescribing information, with administration occurring twice daily for 6 weeks.

To maintain remission of ulcerative colitis, adults should take 1.6 grams, equivalent to four 400 mg capsules, daily. This dosage should be divided into two to four separate doses throughout the day.

It is critical to note that two MESALAMINE delayed-release 400 mg capsules should not be substituted for one mesalamine delayed-release 800 mg tablet.

Contraindications

Use of MESALAMINE delayed-release capsules is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates, or to any of the components of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Healthcare professionals should exercise caution when prescribing MESALAMINE delayed-release capsules, particularly in patients with renal impairment or those taking nephrotoxic medications. It is imperative to assess renal function at the initiation of treatment and periodically thereafter. The risks and benefits of continuing therapy in patients with known renal impairment must be carefully evaluated, and renal function should be monitored closely. If there is any deterioration in renal function, MESALAMINE delayed-release capsules should be discontinued.

Patients should be monitored for symptoms indicative of Mesalamine-induced Acute Intolerance Syndrome, which may mimic an exacerbation of ulcerative colitis. If such symptoms worsen during treatment, it is essential to discontinue the medication and consider alternative management strategies.

Hypersensitivity reactions, including myocarditis and pericarditis, necessitate immediate evaluation and discontinuation of MESALAMINE delayed-release capsules if suspected. Additionally, the use of these capsules in patients with known liver impairment should be approached with caution, weighing the potential risks against the benefits.

In cases of severe cutaneous adverse reactions or other signs of hypersensitivity, treatment should be stopped at the first indication, and further evaluation should be considered. Patients with pre-existing skin conditions are advised to minimize sun exposure, wear protective clothing, and apply a broad-spectrum sunscreen when outdoors to mitigate the risk of skin reactions.

Adequate fluid intake is crucial during treatment, as mesalamine-containing stones may not be detectable through standard radiography or computed tomography (CT). Furthermore, healthcare providers should consider the iron content of MESALAMINE delayed-release capsules in patients who are receiving iron supplementation or are at risk for iron overload.

It is important to note that the use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine via liquid chromatography with electrochemical detection. Therefore, an alternative, selective assay for normetanephrine should be considered due to the similarity in chromatograms between normetanephrine and mesalamine's main metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA).

In summary, careful monitoring and evaluation of patients are essential to ensure the safe use of MESALAMINE delayed-release capsules, with particular attention to renal function, hypersensitivity reactions, and potential interactions with laboratory tests.

Side Effects

Adverse reactions observed in clinical trials and postmarketing experiences have been categorized based on their seriousness and frequency.

Common adverse reactions (≥5%) reported in adults include eructation, abdominal pain, constipation, dizziness, rhinitis, back pain, and rash. In pediatric patients, common adverse reactions (≥5%) consist of nasopharyngitis, headache, abdominal pain, dizziness, sinusitis, rash, cough, and diarrhea.

In clinical trials involving adults, several adverse reactions led to withdrawal from the study, including diarrhea, colitis flare, dizziness, nausea, joint pain, and headache. In pediatric participants aged 5 to 17 years, serious adverse reactions were noted, such as sinusitis, adenovirus infection, pancreatitis, abdominal pain, decreased body mass index, bloody diarrhea, sclerosing cholangitis, anemia, and syncope.

Postmarketing experiences have revealed additional adverse reactions across various systems. Notable reactions include neck pain, facial edema, and lupus-like syndrome under the body as a whole. Cardiovascular events such as pericarditis and myocarditis have also been reported. Endocrine-related adverse reactions include nephrogenic diabetes insipidus.

Gastrointestinal adverse reactions encompass anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer, and bloody diarrhea. Hematologic reactions include agranulocytosis, aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, and lymphadenopathy. Musculoskeletal reactions such as gout have been documented.

Nervous system-related adverse reactions include depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome, and intracranial hypertension. Renal adverse reactions consist of renal failure, interstitial nephritis, minimal change disease, and nephrolithiasis.

Respiratory and pulmonary adverse reactions include eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, and pleurisy/pleuritis. Skin reactions reported include alopecia, psoriasis, pyoderma gangrenosum, dry skin, erythema nodosum, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).

Adverse reactions affecting special senses include eye pain, taste perversion, blurred vision, and tinnitus. Urogenital adverse reactions reported include dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, and reversible oligospermia.

Laboratory abnormalities associated with the use of this medication include elevated levels of AST (SGOT) or ALT (SGPT), alkaline phosphatase, GGT, LDH, bilirubin, serum creatinine, and BUN.

Drug Interactions

Nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), may increase the risk of nephrotoxicity when used concurrently. It is advisable to monitor renal function and observe for any mesalamine-related adverse reactions in patients receiving these agents.

Concomitant use of azathioprine or 6-mercaptopurine is associated with an increased risk of blood disorders. Regular monitoring of complete blood cell counts and platelet counts is recommended to detect any potential hematological complications.

Packaging & NDC

The table below lists all NDC Code configurations of Mesalamine, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of MESALAMINE delayed-release capsules for the treatment of mildly to moderately active ulcerative colitis in pediatric patients aged 5 to 17 years have been established through adequate and well-controlled studies utilizing mesalamine delayed-release 400 mg tablets. Evidence supporting the use of MESALAMINE delayed-release capsules in this age group is derived from both adult studies and a specific 6-week study involving 82 pediatric patients within the same age range.

However, the safety and effectiveness of MESALAMINE delayed-release capsules for treating mildly to moderately active ulcerative colitis in pediatric patients under the age of 5 years have not been established. Additionally, the safety and effectiveness of these capsules for the maintenance of remission of ulcerative colitis in pediatric patients remain unproven.

Geriatric Use

Clinical studies of mesalamine delayed-release tablets did not include a sufficient number of patients aged 65 years and older to determine whether they respond differently than younger patients. However, reports from uncontrolled clinical studies and postmarketing experience indicate a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia, in geriatric patients receiving mesalamine delayed-release tablets compared to younger patients taking mesalamine-containing products such as mesalamine delayed-release capsules.

Due to these findings, it is essential to monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine delayed-release capsules. Additionally, when prescribing mesalamine to geriatric patients, healthcare providers should consider the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may affect treatment outcomes. Careful assessment and monitoring are recommended to ensure the safety and efficacy of mesalamine in this population.

Pregnancy

There are no adequate and well-controlled studies of MESALAMINE delayed-release capsules in pregnant women. Limited published human data indicate that the use of mesalamine does not increase the overall rate of congenital malformations. However, some studies suggest an increased rate of preterm birth, stillbirth, and low birth weight; it remains unclear whether these adverse pregnancy outcomes are attributable to mesalamine exposure, underlying maternal disease, or both, as active inflammatory bowel disease is also associated with such outcomes.

All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. In animal reproduction studies, mesalamine was administered to rats and rabbits during organogenesis at oral doses up to 480 mg/kg/day, with no evidence of fetal harm observed. Specifically, doses approximately 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose did not demonstrate any adverse effects on fetal development or fertility.

Mesalamine crosses the placenta, and therefore, it should be used during pregnancy only if clearly needed. In prospective and retrospective studies involving over 600 women exposed to mesalamine during pregnancy, the observed rate of congenital malformations did not exceed the background rate found in the general population. Given the potential risks, healthcare providers should carefully consider the benefits and risks of mesalamine therapy in pregnant patients.

Lactation

Mesalamine and its N-acetyl metabolite are excreted in human milk. In published lactation studies, maternal doses of mesalamine from various oral and rectal formulations ranged from 500 mg to 3 g daily. The concentration of mesalamine in breast milk has been reported to range from non-detectable to 0.11 mg/L, while the concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L.

Based on these concentrations, the estimated daily doses for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid.

When considering the use of MESALAMINE delayed-release capsules in lactating mothers, it is important to weigh the developmental and health benefits of breastfeeding against the mother's clinical need for the medication and any potential adverse effects on the breastfed infant from the drug or the underlying maternal condition. Caution should be exercised when administering MESALAMINE delayed-release capsules to nursing women.

Renal Impairment

Renal impairment, including conditions such as minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients taking MESALAMINE delayed-release capsules. It is essential to evaluate renal function prior to the initiation of MESALAMINE delayed-release capsules and to monitor it periodically during therapy. If renal function deteriorates while on treatment, MESALAMINE delayed-release capsules should be discontinued. Additionally, healthcare professionals should carefully assess the risks and benefits of using MESALAMINE delayed-release capsules in patients with known renal impairment, a history of renal disease, or those taking concomitant nephrotoxic drugs.

Hepatic Impairment

Patients with hepatic impairment may experience an increased risk of hepatic failure when administered mesalamine. It is essential for healthcare providers to carefully evaluate the risks and benefits of using mesalamine delayed-release capsules in this population.

Due to the potential for adverse effects on liver function, close monitoring of liver parameters is recommended for patients with pre-existing liver disease who are prescribed mesalamine. Regular assessment of liver function tests should be conducted to ensure patient safety and to identify any signs of hepatic deterioration promptly.

In summary, the use of mesalamine delayed-release capsules in patients with known liver impairment requires a thorough evaluation of the individual patient's condition, along with vigilant monitoring of liver function throughout the treatment course.

Overdosage

In the event of an overdose of MESALAMINE delayed-release capsules, which is classified as an aminosalicylate, healthcare professionals should be vigilant for symptoms indicative of salicylate toxicity. Common manifestations include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and various neurologic symptoms such as headache, dizziness, confusion, and seizures.

Severe cases of salicylate intoxication may result in significant electrolyte and blood pH imbalances, with the potential for involvement of other organs, including renal and hepatic systems. It is crucial to recognize these complications early to mitigate further risks.

Currently, there is no specific antidote available for mesalamine overdose. However, conventional therapeutic approaches for managing salicylate toxicity may be beneficial in cases of acute overdosage. These interventions typically include gastrointestinal tract decontamination to limit further absorption of the drug.

Management should also focus on correcting any fluid and electrolyte imbalances through the administration of appropriate intravenous therapy. Maintaining adequate renal function is essential during the treatment process.

It is important to note that MESALAMINE delayed-release capsules are a pH-dependent delayed-release formulation. This characteristic should be taken into account when devising a treatment plan for suspected overdose cases, as it may influence the pharmacokinetics and overall management strategy.

Nonclinical Toxicology

Carcinogenesis: Mesalamine was not found to be carcinogenic in studies conducted with dietary doses of up to 480 mg/kg/day in rats and 2000 mg/kg/day in mice. These doses correspond to approximately 2.9 and 6.1 times the maximum recommended maintenance dose of mesalamine delayed-release capsules, which is 1.6 grams per day or 26.7 mg/kg/day based on a 60 kg body weight.

Mutagenesis: In mutagenicity assessments, mesalamine yielded negative results in the Ames assay. Additionally, it did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in vitro, nor did it induce micronuclei in mouse bone marrow polychromatic erythrocytes.

Impairment of Fertility: Mesalamine, administered at oral doses up to 480 mg/kg/day, approximately 1.9 times the recommended human treatment dose on a body surface area basis, demonstrated no adverse effects on the fertility or reproductive performance of male and female rats.

Animal Toxicology: In animal studies involving rats, mice, and dogs, the kidney was identified as the principal organ affected by toxicity. Mesalamine caused renal papillary necrosis in rats at single doses ranging from approximately 750 mg/kg to 1000 mg/kg, which is about 3 to 4 times the recommended human dose based on body surface area. Chronic administration of doses of 170 and 360 mg/kg/day, approximately 0.7 and 1.5 times the recommended human dose, respectively, for six months resulted in renal pathologies including papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia. In mice, oral doses of 4000 mg/kg/day of mesalamine, approximately 8 times the recommended human dose based on body surface area, administered for three months led to tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis. In dogs, a single dose of 6000 mg, about 8 times the recommended human dose based on body surface area, of delayed-release mesalamine tablets resulted in renal papillary necrosis, although this was not fatal. Chronic administration of mesalamine at doses of 80 mg/kg/day, approximately 1.1 times the recommended human dose based on body surface area, also resulted in renal changes in dogs.

Postmarketing Experience

During post-approval use of MESALAMINE delayed-release capsules and other mesalamine-containing products, various adverse reactions have been reported voluntarily or through surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Reports include neck pain, facial edema, general edema, lupus-like syndrome, and drug fever.

Cardiovascular: Cases of pericarditis and myocarditis have been documented.

Endocrine: Instances of nephrogenic diabetes insipidus have been noted.

Gastrointestinal: Adverse events such as anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer, and bloody diarrhea have been reported.

Hematologic: Reports of agranulocytosis, aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, and lymphadenopathy have been observed.

Musculoskeletal: Gout has been identified as a reported reaction.

Nervous System: Adverse events include depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome, and intracranial hypertension.

Renal: Cases of renal failure, interstitial nephritis, minimal change disease, and nephrolithiasis have been reported.

Respiratory/Pulmonary: Reports include eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, and pleurisy/pleuritis.

Skin: Adverse reactions such as alopecia, psoriasis, pyoderma gangrenosum, dry skin, erythema nodosum, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been documented.

Special Senses: Reports of eye pain, taste perversion, blurred vision, and tinnitus have been noted.

Urogenital: Instances of dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, and reversible oligospermia have been reported.

Additionally, urine discoloration has been observed ex-vivo due to contact of mesalamine, including its inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.

Laboratory Abnormalities: Elevated levels of AST (SGOT), ALT (SGPT), alkaline phosphatase, GGT, LDH, bilirubin, serum creatinine, and BUN have been reported.

Patient Counseling

Patients should be informed that if they are transitioning from a previous oral mesalamine therapy to MESALAMINE delayed-release capsules, they must discontinue their prior oral mesalamine therapy and adhere to the dosing instructions for MESALAMINE delayed-release capsules. It is important to clarify that two MESALAMINE delayed-release 400 mg capsules cannot be substituted for one mesalamine delayed-release 800 mg tablet.

Patients may take MESALAMINE delayed-release capsules with or without food. They should be instructed to swallow the capsules whole and not to cut, break, crush, or chew them. For those who have difficulty swallowing the capsules whole, they can carefully open the capsules and swallow the contents, which consist of four 100 mg tablets. Patients should open the number of capsules necessary to achieve a complete dose, ensuring that all tablets from each capsule are swallowed without retention in the mouth. The tablets should also be swallowed whole, without cutting, breaking, crushing, or chewing.

It is advisable for patients to drink an adequate amount of fluids while taking this medication. They should be made aware that intact, partially intact, and/or tablet shells may be observed in their stool and should contact their healthcare provider if this occurs repeatedly.

Patients should also be informed that their urine may become discolored reddish-brown while taking MESALAMINE delayed-release capsules, particularly when it comes into contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is noted, they should observe their urine flow and report to their healthcare provider only if the urine is discolored upon leaving the body, prior to contact with any surface or water (e.g., in the toilet).

Finally, patients should be instructed to protect MESALAMINE delayed-release capsules from moisture by keeping the container tightly closed and ensuring that any desiccant pouches present in the bottle remain with the capsules.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 20° to 25° C (68° to 77° F). Temporary excursions in temperature are permissible, ranging from 15° to 30° C (59° to 86° F). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Use of MESALAMINE delayed-release capsules may result in spuriously elevated urinary normetanephrine test results due to the similarity in chromatograms between normetanephrine and mesalamine's main metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Clinicians should consider utilizing an alternative, selective assay for accurate measurement of normetanephrine.

Postmarketing experience has identified various adverse reactions associated with MESALAMINE delayed-release capsules and other mesalamine-containing products. Reported reactions include neck pain, facial edema, lupus-like syndrome, and drug fever among general body reactions. Cardiovascular issues such as pericarditis and myocarditis, endocrine disorders like nephrogenic diabetes insipidus, and gastrointestinal complications including pancreatitis and bloody diarrhea have also been noted. Hematologic effects may include agranulocytosis and thrombocytopenia, while musculoskeletal reactions can involve gout. Neurological symptoms such as depression and peripheral neuropathy, renal complications like renal failure, and respiratory issues including eosinophilic pneumonia have been documented. Skin reactions range from alopecia to severe conditions like Stevens-Johnson syndrome. Additionally, patients may experience urogenital symptoms such as dysuria and hematuria, and laboratory abnormalities may present as elevated liver enzymes and serum creatinine. Urine discoloration may occur due to contact with hypochlorite-treated surfaces.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Mesalamine as submitted by Greenstone LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)